Stereodependent inhibition of plasminogen activator inhibitor type 1 by phosphorothioate oligonucleotides: proof of sequence specificity in cell culture and in vivo rat experiments.
Hexadecadeoxyribonucleotides complementary to a fragment of human PAI-1 mRNA located upstream of the start codon and their phosphorothioate analogs were studied in cultured HUVECs as sequence-dependent inhibitors of PAI-1 expression. The activity of the random mixture of diastereomers of phosphorothioate hexadecanucleotide PS-16H has been compared with that of isosequential, stereoregular [All-Sp] and [All-Rp] isomers. The highest inhibitory effect on PAI-1 synthesis was observed with the [All-Sp] diastereomer. Stereorandom phosphorothioate oligonucleotide PS-16R complementary to the same region of rat PAI-1 mRNA, when injected into tail vein of rats, substantially decreased the level of PAI-1 in blood plasma.
Stec
W J
WJ
Polish Academy of Sciences, Centre of Molecular and Macromolecular Studies, Department of Bioorganic Chemistry, Lódź.
Cierniewski
C S
CS
Okruszek
A
A
Kobylańska
A
A
Pawłowska
Z
Z
Koziołkiewicz
M
M
Pluskota
E
E
Maciaszek
A
A
Rebowska
B
B
Stasiak
M
M
D000818:Animals; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008297:Male; D009943:Organophosphorus Compounds / Q000737:chemistry; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D013873:Thionucleotides / Q000737:chemistry / Q000494:pharmacology*
D009943:Organophosphorus Compounds; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D013873:Thionucleotides